Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells
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Updated: Jun 5, 2025
Cell Labeling and Targeting with Superparamagnetic Iron Oxide Nanoparticles
Published on: October 19, 2015
Maciej Wnuk1, Susel Del Sol-Fernández2, Dominika Błoniarz1
1Institute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, Rzeszow 35-310, Poland.
Abstract:
The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.
Insights
Researchers developed a novel nanoplatform targeting senescent cells, which accumulate in aging and cancer. This nanoplatform, MNP@CD26@17D, effectively eliminates senescent cells via apoptosis and ferroptosis, offering a promising antiaging and anticancer strategy.
Area of Science:
- Biomedical Engineering
- Cellular Biology
- Pharmacology
Background:
- Cellular senescence, a state of irreversible growth arrest, contributes to aging and age-related diseases.
- Senescent cells also emerge as a consequence of cancer therapies, fostering drug resistance and treatment failure.
- Current senolytic therapies face limitations, necessitating the development of targeted and validated approaches.
Purpose of the Study:
- To design and evaluate a novel nanoplatform for targeted senescent cell elimination.
- To investigate the efficacy of the nanoplatform against senescent cells induced by oxidative stress and anticancer drugs.
- To identify CD26 as a potential cell surface marker for senescent cancer cells.
Main Methods:
- Fabrication of a nanoplatform using iron oxide nanoparticles functionalized with an anti-CD26 antibody and loaded with the senolytic drug 17-DMAG (MNP@CD26@17D).
- Assessment of MNP@CD26@17D efficacy on oxidative stress-induced senescent human fibroblasts (WI-38, BJ) and anticancer drug-induced senescent A431 cells.
- Analysis of cellular responses, including apoptosis and ferroptosis, following MNP@CD26@17D treatment, and investigation of the underlying ferroptosis mechanism (ferritinophagy).
Main Results:
- Demonstrated CD26 as a valid senescence marker in cancer cells.
- Observed a dual response in senescent cells: early apoptosis (2h) and late ferroptosis (24h) upon MNP@CD26@17D treatment.
- Evidence suggests MNP@CD26@17D-induced ferroptosis involves ferritinophagy, indicated by elevated NCOA4 and reduced ferritin levels.
- No hemolysis observed in human erythrocytes after 24h treatment, suggesting good hemocompatibility.
Conclusions:
- The MNP@CD26@17D nanoplatform effectively targets and eliminates senescent cells, including those resistant to apoptosis.
- CD26 is validated as a senescent cell marker, particularly in cancer cells.
- The nanoplatform induces senescent cell death through a dual mechanism of apoptosis and ferroptosis, with ferroptosis potentially mediated by ferritinophagy.
- This nanoplatform represents a promising multifunctional tool for targeting senescent skin cells and overcoming apoptosis resistance in antiaging and anticancer strategies.
